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The S-(−)- and R-(+)-nicotine isomers were administered subcutaneously via Alzet osmotic pumps to male Hartley guinea-pigs (n = 5 with each isomer) over a 23-day period. Estimated dosage rate throughout the experiment was 0.6 mg−1. Urine samples were collected over this time and the levels of urinary oxidative and N-methylated nicotine metabolites were measured by cation-exchange HPLC analysis. S-(−)-Nicotine formed only oxidative metabolites, whereas the R-(+)-isomer formed both oxidative and N-methylated metabolites. 3′-Hydroxycotinine and nicotine-1′-oxide were major metabolites of both enantiomers; cotinine and nornicotine were only minor metabolites. The major N-methylated metabolite of R-(+)-nicotine was N-methylnicotinium ion; N-methylcotininium ion and N-methylnornicotinium ion were also identified as metabolites of this nicotine isomer. Total N-methylated quaternary ammonium metabolites accounted for 15 to 20% of the administered dose of R-(+)-nicotine. An interesting enantioselective reduction in the percent of oxidative urinary metabolites formed from S-(−)-nicotine was observed over 23 days. This may indicate the enantioselective induction of an uncharacterized metabolic pathway for this nicotine isomer.

A variety of possible N-oxidation products of 2-methyl-1, 2-bis(3-pyridyl)propan-1-one (metyrapone) have been synthesized by peracid oxidation, and characterized using various spectroscopic techniques. Specific and sensitive chromatographic techniques have been developed for the separation and identification of its in vitro metabolites. Incubation of metyrapone with rat or mouse hepatic microsomes, in the presence of a NADPH-regenerating system, leads to the formation of metyrapol (keto-reduction), and two mono-N-oxides.

The in-vivo metabolism of R-(+)-[3H-N′-CH3; 14C-N-CH3]-N-methylnicotinium acetate (NMN) was studied in the guinea-pig to determine the in-vivo stability of the N-methyl and N′-methyl groups of this primary nicotine metabolite. The results showed that N-demethylation does not occur. However, losses of 34 and 36%, respectively, of the 3H label in the N′-CH3 group of urinary NMN and the secondary metabolite, N-methyl-N′-oxonicotinium ion (NMNO), were observed. These results suggest that biotransformation of NMN may involve either an initial N′-demethylation step to N-methylnornicotinium ion (NMNor) followed by N′-methylation back to NMN, or the formation of an N′-methylene iminium species, which may be reductively converted back to NMN.

Studies using the solute-enhanced phase partition technique demonstrate that the endogenous amines histamine and spermine bind to both salmon sperm DNA and poly(dGdC) in a markedly cooperative fashion. Both compounds exhibited DNA sequence-dependence effects in their mode of binding. The linear aliphatic spermine molecule binds more strongly than histamine to both DNA types.

Incubation of human liver cytosol with either R-(+)-[3H-N′CH3]nicotine or S-(−)-[3H-N′CH3]nicotine results in the formation of the corresponding N-methyl quaternary ammonium metabolite. A substrate stereoselectivity was observed in that the turnover number for the methylation of the S-(−)-isomer was 0.25 pmol mg 1 protein h−1, whereas that for the R-(+)-isomer was 2.11. The latter substrate exhibited an apparent Km value of 20.1 μM. Nicotine N-methylation appears to be species-dependent, since rat liver homogenates contained no ‘nicotine N-methyl-transferase’ activity, whereas with guinea-pig liver homogenates, a substrate specificity for only R-(+)-nicotine was observed.